The polycystic ovary syndrome (PCOS) is the major cause of female factor infertility in the United States. This is in part related to chronic anovulation, and is likely further aggravated by other factors which produce an increased rate of early (i.e., first trimester) pregnancy loss (EPL). It is now recognized that insulin resistance is a prominent feature of PCOS and that it contributes to the anovulation of PCOS, as evidenced by a marked increase in frequency of ovulation with the administration of metformin. In PCOS metformin i) increases frequency of spontaneous ovulation, ii) increases success of induction of ovulation, and iii) increases rate of clinical pregnancy. Studies suggest that insulin resistance also contributes to infertility in PCOS by producing an unfavorable endometrial milieu, and administration of metformin to women with PCOS throughout pregnancy is associated with a 79% reduction in the rate of EPL. The focus of this U54 Subproject is the role of insulin resistance in the infertility of PCOS. The present application proposes two clinical research studies. The first study is a collaborative trial the Reproductive Medicine Network to determine what represents the optimal pharmacologic intervention for initial induction of ovulation in PCOS: metformin monotherapy, clomiphene monotherapy, or simultaneous administration of both metformin and clomiphene. The second study explores the effects of metformin on the reproductive system of both healthy women and women with PCOS, assessing the effects of metformin on i) dynamics of pituitary gonadotropin secretion, ii) adequacy of luteal phase progesterone and other circulating sex steroids, and iii) anatomic endometrial maturation as well as endometrial expression of receptors for sex steroids and integrins. Obtaining this information is critical since physicians are increasingly administering metformin to women with PCOS to facilitate ovulation and pregnancy. In summary, the proposed studies will provide both important translational and mechanistic information. They promise to enhance our understanding of the relationship of insulin resistance to the infertility of PCOS, and to provide useful information that can be directly translated into the clinical care of women with PCOS.